Determinants of Neurodegenerative Decline in Primary Progressive Aphasia

原发性进行性失语症神经退行性衰退的决定因素

• 批准号: 8811483
• 负责人: EMILY J ROGALSKI
• 金额: $ 33.87万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811483
• 关键词: Address; Alzheimer' s Disease; Amyloid; Anatomy; Area; Atrophic; Autopsy; Benchmarking; Biological Markers; Biometry; Brain; Brain Diseases; Clinical; Clinical Treatment; Clinical Trials; Cognitive; Collaborations; Comprehension; Data; Dementia; Development; Differential Diagnosis; Disease; Disease Marker; Disease Progression; Elderly; Etiology; Family; Frontotemporal Lobar Degenerations; Funding; Future; Goals; Image; Impaired cognition; Impairment; Individual; Investigation; Knowledge; Language; Letters; Life; Location; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Measures; Medial; Memory Loss; Methods; Monitor; National Institute on Deafness and Other Communication Disorders; Nature; Nerve Degeneration; Neurobiology; Neuropsychological Tests; Neuropsychology; Outcome; Outcome Measure; Pathology; Patients; Pattern; Performance; Phenotype; Physics; Population; Positron-Emission Tomography; Primary Progressive Aphasia; Procedures; Radiopharmaceuticals; Reporting; Research Personnel; Series; Severities; Site; Staging; Symptoms; Syndrome; Testing; Therapeutic; Therapeutic Trials; Time; Universities; Variant; Visit; amyloid imaging; base; cerebral atrophy; clinical phenotype; clinically relevant; cognitive change; cognitive performance; functional decline; high risk; in vivo; interest; longitudinal course; mild cognitive impairment; neurobehavior; neuroimaging; neuropathology; neuropsychological; normal aging; novel therapeutics; patient expectation; success; time interval; treatment effect; treatment strategy; treatment trial

DESCRIPTION (provided by applicant): Primary progressive aphasia (PPA) is a clinical dementia syndrome caused by neurodegenerative brain disease, with language impairment as the primary feature. Although functional decline invariably occurs, the factors influencing the time course of decline and severity of symptoms in PPA have not been fully elucidated. Furthermore, PPA is associated with two main classes of underlying pathology: Alzheimer pathology (PPA-AD) and frontotemporal lobar degeneration (PPA-FTLD) pathology, but there is currently no reliable in vivo method for identifying the nature of the pathology. Numerous autopsy series, including one from our Center, indicate that approximately 30% of cases with the PPA phenotype have PPA-AD pathology while the other 70% show PPA-FTLD pathology. However, the reliable identification of clinical and anatomical features of underlying pathology in living patients remains an ongoing challenge. The proposed studies are directed at establishing potential markers for disease etiology and progression. The Specific Aims include: 1) To follow 40 patients with the PPA syndrome using MR imaging at 6-month intervals over an 18-month time period to quantify and characterize how brain atrophy changes over time; 2) to determine the temporal relationship between cognitive change and the quantity and location of atrophy; and 3) to use the new [18F]-AV-45 PET imaging compound to identify amyloid burden in PPA patients as a marker of AD pathology and to identify its relationship to atrophy. Longitudinal rates of regional (i.e., medial temporal) atrophy have been useful in predicting cognitive decline in the amnestic dementia of the Alzheimer's type. Therefore, we predict that atrophy rates in language related brain areas will be useful in differential diagnosis and monitoring of disease progression in PPA, potentially pointing the way to an outcome measure for clinical trials. The clinical, cognitive and anatomical features associated with amyloid burden will be identified. Data from this project will determine whether the temporal progression of atrophy is related to cognitive decline, anatomical site of primary atrophy, or putative underlying pathology based on amyloid burden. This project represents the first multidimensional study of longitudinal course using the new antemortem amyloid biomarker [18F]-AV-45 in PPA. In addition to their theoretical interest, the results from this study are of crucial importance for defining objective biomarkers of disease type and progression, which will inform therapeutic treatment strategies for this relatively underserved dementia population. Results from this project will also fill gaps n our knowledge of the relationship between atrophy patterns and both clinical progression and underlying pathology in patients with PPA. The approach in Aim 1 is driven by atrophy patterns and free of clinical bias, while Aims 2 and 3 consider the relationship with cognitive performance and amyloid positivity, respectively. This is of considerable importance for increasing the accuracy with which we assign patients to therapeutic trials.

描述（申请人提供）：原发性进行性失语症（PPA）是一种由神经退行性脑病引起的临床痴呆综合征，以语言障碍为主要特征。虽然功能下降总是发生，影响PPA的下降和症状的严重程度的时间过程的因素还没有完全阐明。此外，PPA与两种主要类别的潜在病理学相关：阿尔茨海默病病理学（PPA-AD）和额颞叶变性（PPA-FTLD）病理学，但目前没有可靠的体内方法用于鉴定病理学的性质。许多尸检系列，包括我们中心的一个，表明大约30%的PPA表型病例有PPA-AD病理，而其他70%的病例显示PPA-FTLD病理。然而，可靠的临床和解剖特征的基础病理识别， 活着的病人仍然是一个持续的挑战。拟议的研究旨在建立疾病病因和进展的潜在标志物。具体目标包括：1）在18个月的时间内，使用MR成像以6个月的间隔跟踪40名PPA综合征患者，以量化和表征脑萎缩如何随时间变化; 2）确定认知变化与萎缩的数量和位置之间的时间关系;和3）使用新的[18F]-AV-45 PET成像化合物来鉴定PPA患者中的淀粉样蛋白负荷作为AD病理学的标志物，并鉴定其与萎缩的关系。区域纵向比率（即，内侧颞叶）萎缩在预测阿尔茨海默型遗忘性痴呆的认知能力下降方面是有用的。因此，我们预测语言相关脑区的萎缩率将有助于鉴别诊断和监测PPA的疾病进展，可能为临床试验的结果指标指明方向。将确定与淀粉样蛋白负荷相关的临床、认知和解剖学特征。本项目的数据将确定萎缩的时间进展是否与认知能力下降、原发性萎缩的解剖部位或基于淀粉样蛋白负荷的假定基础病理学相关。该项目代表了在PPA中使用新的死前淀粉样蛋白生物标志物[18 F]-AV-45的纵向过程的第一个多维研究。除了他们的理论兴趣之外，这项研究的结果对于定义疾病类型和进展的客观生物标志物至关重要，这将为这个相对缺乏服务的痴呆人群提供治疗策略。该项目的结果也将填补我们对PPA患者萎缩模式与临床进展和基础病理学之间关系的知识空白。目的1中的方法由萎缩模式驱动，无临床偏倚，而目的2和3分别考虑了与认知表现和淀粉样蛋白阳性的关系。这对于提高我们将患者分配到治疗试验的准确性具有相当重要的意义。